王建竹, 孔祥英, 林 娜

(中國中醫(yī)科學(xué)院中藥研究所， 北京 100700)

ERK信號轉(zhuǎn)導(dǎo)通路與類風(fēng)濕關(guān)節(jié)炎*

王建竹, 孔祥英, 林 娜△

(中國中醫(yī)科學(xué)院中藥研究所， 北京 100700)

細(xì)胞外信號調(diào)節(jié)激酶類; 關(guān)節(jié)炎，類風(fēng)濕

絲裂原活化蛋白激酶(mitogen-activated protein kinases，MAPKs)信號轉(zhuǎn)導(dǎo)通路是細(xì)胞外信號引起細(xì)胞核內(nèi)反應(yīng)的重要通路，而細(xì)胞外信號調(diào)節(jié)激酶(extracellular signal-regulated kinase, ERK)通路是MAPKs家族中的重要成員，其異?；罨c類風(fēng)濕關(guān)節(jié)炎(rheumatoid arthritis，RA)關(guān)節(jié)破壞的病理過程密切相關(guān)。

1 ERK信號轉(zhuǎn)導(dǎo)通路的活化與生理功能

MAPKs家族是一類高度保守的蘇氨酸/酪氨酸蛋白激酶，可通過嚴(yán)格的3級酶促級聯(lián)反應(yīng)(MAPKKK→MAPKK→MAPK)激活，進(jìn)而調(diào)節(jié)特定基因的表達(dá)。ERK是MAPKs家族中的一員，可被炎癥因子、絲裂原、生長因子等激活，對細(xì)胞的生長、增殖、分化、存活等發(fā)揮重要作用[1，2]。

研究證實(shí)，受體酪氨酸激酶、G蛋白偶聯(lián)受體和某些細(xì)胞因子受體均可激活ERK信號轉(zhuǎn)導(dǎo)通路。多數(shù)信號因子對ERK的活化都始于對Ras的激活，活化的Ras可進(jìn)一步與絲/蘇氨酸蛋白激酶Raf的氨基端結(jié)合并使其激活。Raf可磷酸化激活MEK1/MEK2，進(jìn)而高度選擇性活化ERK1和ERK2(即p44 MAPK和p42 MAPK)。G蛋白偶聯(lián)受體(G protein-coupled receptors，GPCRs)也可通過一系列復(fù)雜的級聯(lián)反應(yīng)影響ERK活化。此外某些細(xì)胞因子受體可通過激活JAK、磷酸化Shc進(jìn)而激活ERK。而負(fù)反饋調(diào)節(jié)則是保證MAPKs不持續(xù)活化的重要機(jī)制，MAPKs可以至少誘導(dǎo)產(chǎn)生3種不同的蛋白磷酸酶以抑制MAPK活化，分別為二元特異性磷酸酶、蘇氨酸磷酸酶和酪氨酸磷酸酶[3-5]。

活化的ERK可作用于多種底物，如p90核糖體蛋白S6激酶(90 kD ribosomal protein S6 kinase, p90 RSK) 、磷脂酶A2和微管相關(guān)蛋白等。作用底物的多樣化，決定了ERK功能的多樣性。有研究表明T細(xì)胞被RA相關(guān)抗原激活后的增殖有賴于ERK的活化，ERK的特異性抑制劑PD98059可抑制由血清、佛波酯或生長因子導(dǎo)致的細(xì)胞增殖，也能抑制耳腫脹模型小鼠和實(shí)驗(yàn)性骨關(guān)節(jié)炎模型兔的炎癥反應(yīng)。除介導(dǎo)細(xì)胞增殖和炎癥反應(yīng)外，ERK1/2信號通路還參與調(diào)控細(xì)胞的存活，活化的MEK1和MEK2等位基因可促進(jìn)細(xì)胞存活，而其基因突變則抑制細(xì)胞存活。

2 ERK通路在RA關(guān)節(jié)破壞中的生物學(xué)效應(yīng)

滑膜組織炎性增生、關(guān)節(jié)軟骨和骨進(jìn)行性破壞是RA關(guān)節(jié)破壞的病理環(huán)節(jié)，ERK通路可能參與并部分介導(dǎo)了上述病理過程。

2.1ERK信號通路與RA滑膜炎癥 滑膜組織炎性浸潤、滑膜細(xì)胞異常增殖和血管翳形成是RA滑膜病變的重要特征。免疫組織化學(xué)分析結(jié)果顯示ERK在RA滑膜組織的T淋巴細(xì)胞、成纖維樣細(xì)胞和巨噬細(xì)胞中明顯活化[6]，這一事實(shí)提示ERK參與RA受累滑膜組織病理信號的轉(zhuǎn)導(dǎo)。

細(xì)胞增殖或凋亡及多種細(xì)胞因子的轉(zhuǎn)錄和合成等一系列生物效應(yīng)是由病理信號的級聯(lián)轉(zhuǎn)導(dǎo)介導(dǎo)的。研究表明ERK通路活化促進(jìn)T細(xì)胞的增殖及多種細(xì)胞因子的分泌，進(jìn)而引起單核細(xì)胞和巨噬細(xì)胞的聚集和活化[7,8]。RA滑膜組織中活化的單核細(xì)胞和巨噬細(xì)胞可進(jìn)一步分泌腫瘤壞死因子(tumor necrosis factor，TNF)-α、IL(interleukin，IL)-1β和IL-6等多種炎癥細(xì)胞因子，進(jìn)而誘導(dǎo)滑膜組織產(chǎn)生IL-8、基質(zhì)金屬蛋白酶(matrix metalloproteinase，MMP)和黏附分子等多種生物小分子，促進(jìn)RA成纖維樣滑膜細(xì)胞過度增殖和凋亡異常。

促炎細(xì)胞因子誘導(dǎo)的滑膜增生，是成纖維樣滑膜細(xì)胞增殖和凋亡失衡的結(jié)果。巨噬細(xì)胞游走抑制因子(macrophage migration inhibitory factor，MIF) 是表達(dá)于RA成纖維樣滑膜細(xì)胞及巨噬細(xì)胞的促炎細(xì)胞因子。腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體(TNF-related apoptosis-inducing ligand，TRAIL)被認(rèn)為是一種促RA成纖維滑膜細(xì)胞凋亡的因子。研究發(fā)現(xiàn)MIF和TRAIL都可通過ERK活化促進(jìn)滑膜細(xì)胞增殖[9]。血清淀粉樣蛋白A(serum amyloid A，SAA)是一種重要的急性期反應(yīng)蛋白，可以調(diào)節(jié)炎癥細(xì)胞反應(yīng)。研究表明RA患者滑膜細(xì)胞、滑液及血清中SAA水平明顯升高，且其含量與RA活動性呈明顯正相關(guān)。Lee等[11]研究證實(shí)SAA與其受體FPRL1結(jié)合能顯著刺激RA成纖維樣滑膜細(xì)胞增殖并抑制其凋亡，同時(shí)他們還發(fā)現(xiàn)SAA的這種作用與誘導(dǎo)ERK和Akt活化，進(jìn)而引起下游細(xì)胞周期蛋白D1和Bcl-2水平升高密切相關(guān)。血管生成素1(angiopoietin 1，Ang-1)及特異性酪氨酸激酶受體(Tie-2 )在RA滑膜組織中大量表達(dá)[10]，且介導(dǎo)RA血管翳形成和關(guān)節(jié)結(jié)構(gòu)破壞。研究表明，Ang-1/Tie-2能促進(jìn)RA滑膜細(xì)胞增殖并抑制其凋亡，其機(jī)制與提高ERK活性相關(guān)[12]。血管內(nèi)皮生長因子(vascular endothelial growth factor，VEGF) 是一種重要的細(xì)胞存活因子，在RA滑液及滑膜細(xì)胞中呈高表達(dá)狀態(tài)。VEGF165與其受體NP-1特異性結(jié)合也可活化ERK和絲氨酸/蘇氨酸激酶Akt，提高Bcl-2水平，抑制滑膜細(xì)胞的凋亡[13]。

異常增殖的RA細(xì)胞過表達(dá)基質(zhì)降解酶如MMP-1、MMP-3等[14]，水解周圍組織，破壞關(guān)節(jié)結(jié)構(gòu)，同時(shí)也利于表皮細(xì)胞的遷移和毛細(xì)管的形成[15]，為新生血管的形成提供了條件。另外MMP-2、MMP-9及膜型MMPs對血管發(fā)生也具有重要作用[16]。MMPs的表達(dá)受多種因素的調(diào)控。Pap等[17]研究發(fā)現(xiàn)c-Raf-1和c-Myc顯性負(fù)突變的滑膜細(xì)胞，ERK及c-Jun磷酸化水平顯著下降，MMP-1、MMP-3轉(zhuǎn)錄水平降低。同時(shí)還有研究發(fā)現(xiàn)環(huán)氧化酶-2衍生的前列腺素E可通過抑制ERK而下調(diào)滑膜成纖維細(xì)胞MMP-1表達(dá)[18]。整體動物實(shí)驗(yàn)中抑制c-Raf-1和c-Myc可明顯減少RA成纖維樣滑膜細(xì)胞對SCID鼠模型軟骨的降解[17]。其中c-Raf-1是ERK的上游分子，而c-Myc、c-Jun則是ERK信號通路下游的轉(zhuǎn)錄因子，據(jù)此可推測ERK活化介導(dǎo)RA成纖維樣滑膜細(xì)胞MMPs表達(dá)的調(diào)節(jié)。此外Han等[19]研究證實(shí)抑制ERK活化，可下調(diào)IL-1誘導(dǎo)的RA成纖維樣滑膜細(xì)胞AP-1活化和MMP-1的產(chǎn)生，由此推測ERK介導(dǎo)的MMP合成與AP-1活化關(guān)系密切。

可見，RA滑膜成纖維樣細(xì)胞ERK的異?；罨纱龠M(jìn)滑膜細(xì)胞炎癥反應(yīng)，并參與滑膜細(xì)胞過度增殖及凋亡抑制，同時(shí)可增加基質(zhì)降解酶的產(chǎn)生，在關(guān)節(jié)破壞方面發(fā)揮重要作用。

2.2ERK信號通路與RA軟骨破壞 軟骨破壞是RA關(guān)節(jié)損傷的一個(gè)重要病理環(huán)節(jié)。過度增生的炎性滑膜組織侵襲是引起關(guān)節(jié)軟骨破壞的關(guān)鍵因素。研究表明，在SCID鼠軟骨侵蝕實(shí)驗(yàn)中，異常增殖的成纖維樣滑膜細(xì)胞分泌基質(zhì)降解酶如MMPs等，引起細(xì)胞周圍結(jié)構(gòu)破壞是滑膜侵襲軟骨的前提。而ERK通路參與介導(dǎo)了滑膜細(xì)胞MMPs的表達(dá)，那么在RA軟骨細(xì)胞中ERK途徑是否發(fā)揮同樣的作用呢？

MMP-1和MMP-13是介導(dǎo)軟骨破壞的主要MMPs。研究表明基質(zhì)細(xì)胞衍生因子1(stromal cell-derived factor 1，SDF-1)與軟骨細(xì)胞表面特異性受體CXCR4結(jié)合可誘導(dǎo)軟骨細(xì)胞MMP-1的表達(dá)[20]，同時(shí)提高RA軟骨細(xì)胞培養(yǎng)上清液及胞漿中MMP-13蛋白和基因表達(dá)水平，而當(dāng)軟骨細(xì)胞與ERK特異性抑制劑共孵育或在ERK顯性負(fù)突變的軟骨細(xì)胞中，SDF-1均不能升高M(jìn)MP-13的基因轉(zhuǎn)錄水平[21]?？梢奅RK通路參與SDF-1誘導(dǎo)的軟骨細(xì)胞MMP-1和MMP-13的合成。此外，Liacini 等[22]研究發(fā)現(xiàn)TNF-α也可通過活化軟骨細(xì)胞ERK通路，誘導(dǎo)MMP-13的表達(dá)。

綜上，ERK通路介導(dǎo)了RA軟骨細(xì)胞MMPs的表達(dá)，在RA軟骨破壞過程中發(fā)揮重要作用。

2.3ERK信號通路與RA骨破壞 X射線研究顯示骨侵蝕在RA早期階段就出現(xiàn)了，呈進(jìn)行性加重，導(dǎo)致嚴(yán)重的關(guān)節(jié)畸形，最終影響關(guān)節(jié)活動。病理觀察發(fā)現(xiàn)RA患者骨侵蝕區(qū)域及膠原誘導(dǎo)性關(guān)節(jié)炎(collagen-induced arthritis，CIA)大鼠骨破壞部位均可見大量的破骨細(xì)胞，推測凡促進(jìn)破骨細(xì)胞分化、增加破骨細(xì)胞活性及趨化性的因素都可加速RA骨破壞。

研究發(fā)現(xiàn)RA患者異常增殖的滑膜與骨交界面上可見大量破骨細(xì)胞，并出現(xiàn)骨侵蝕，類似現(xiàn)象也發(fā)生在RA動物模型CIA大鼠破壞的關(guān)節(jié)中。研究發(fā)現(xiàn)RA滑膜組織在1,25(OH)2D3和M-CSF存在條件下體外培養(yǎng)3周，可誘導(dǎo)出破骨細(xì)胞，在相似的培養(yǎng)條件下，外周血單核細(xì)胞和RA滑膜細(xì)胞共培養(yǎng)可促進(jìn)單核細(xì)胞向破骨細(xì)胞分化[23，24]。由此推測，異常增殖的滑膜細(xì)胞與破骨細(xì)胞分化相關(guān)，那么RA成纖維樣滑膜細(xì)胞是通過什么信號通路介導(dǎo)破骨細(xì)胞分化呢？研究發(fā)現(xiàn)ERK特異性抑制劑PD98059能劑量依賴性抑制滑膜細(xì)胞RANKL表達(dá)，進(jìn)而抑制破骨細(xì)胞生成。Lee等[25]研究也發(fā)現(xiàn)U0126通過抑制ERK通路，可以減少與滑膜細(xì)胞共培育的單核細(xì)胞向破骨細(xì)胞分化，ERK活性突變體能通過活化Ras/ERK通路，延長破骨細(xì)胞存活時(shí)間。同時(shí)發(fā)現(xiàn)ERK活化可以增加破骨細(xì)胞趨化性[26]。

綜上，ERK信號轉(zhuǎn)導(dǎo)通路可參與破骨細(xì)胞的分化、存活及趨化性的調(diào)節(jié)，在RA關(guān)節(jié)骨破壞過程發(fā)揮重要作用。

3 ERK信號通路與RA相關(guān)其它信號轉(zhuǎn)導(dǎo)通路的關(guān)系

胞內(nèi)各信號通路之間相互影響，形成復(fù)雜的調(diào)控網(wǎng)絡(luò)。研究表明，MAPKs家族的其它成員如c-Jun氨基端激酶(c-Jun NH2-terminal kinases，JNK)、P38、G蛋白偶聯(lián)受體通路及核因子-κB(nuclear factor，NF-κB)通路等均參與RA病理信號的轉(zhuǎn)導(dǎo)，且均與ERK信號通路存在交互作用。

TNF-α、IL-1β可同時(shí)活化RA滑膜組織ERK、JNK和P38等3條MAPKs信號轉(zhuǎn)導(dǎo)通路，Toh等[27]研究發(fā)現(xiàn)JNK特異性抑制劑，而非ERK或P38抑制劑能降低絲裂原活化蛋白激酶磷酸酶(MAPK phosphatase 1，MKP-1)的表達(dá)，進(jìn)而降低ERK和P38的磷酸化水平。NF-κB可調(diào)控TNF-α、IL-6等細(xì)胞因子的轉(zhuǎn)錄和表達(dá)。有報(bào)道表明ERK特異性抑制劑PD98059能抑制RA病人滑膜細(xì)胞NF-κB活性亞基P65核轉(zhuǎn)位[28]，從而抑制多種炎癥細(xì)胞因子如TNF-α、IL-1等的轉(zhuǎn)錄。G蛋白偶聯(lián)受體通路是細(xì)胞外信號引起細(xì)胞核內(nèi)反應(yīng)的通道之一，其中GS、Gi蛋白介導(dǎo)的信號轉(zhuǎn)導(dǎo)通路異常是引起滑膜細(xì)胞功能異常的重要機(jī)制之一。有研究表明，ERK特異性抑制劑U0126能抑制體外培養(yǎng)的CIA大鼠滑膜細(xì)胞rIL-1α誘導(dǎo)引起的Gi蛋白表達(dá)水平的升高。

綜上，ERK通路與MAPKs家族的其它成員、G蛋白偶聯(lián)受體通路及TRAF/NIK/IκBK/NF-κB通路等在RA病理信號的轉(zhuǎn)導(dǎo)過程中存在交互作用，共同構(gòu)成了一個(gè)復(fù)雜的信號轉(zhuǎn)導(dǎo)調(diào)控網(wǎng)絡(luò)，促使RA病情不斷發(fā)展惡化。

4 小結(jié)

ERK參與RA關(guān)節(jié)破壞多個(gè)病理環(huán)節(jié)的信號轉(zhuǎn)導(dǎo)，與RA病理狀態(tài)的維持和病情進(jìn)展密切相關(guān)。深入研究ERK信號轉(zhuǎn)導(dǎo)通路在RA關(guān)節(jié)破壞中的作用，有助于從分子水平深入探討RA的發(fā)病機(jī)制和研制新型藥物。Ohori等[29]研究發(fā)現(xiàn)ERK抑制劑FR180204能顯著抑制CIA大鼠臨床關(guān)節(jié)炎積分，逆轉(zhuǎn)疾病引起的體重下降，降低大鼠抗Ⅱ型膠原抗體的產(chǎn)生，抑制Ⅱ型膠原誘導(dǎo)產(chǎn)生的遲發(fā)型超敏反應(yīng)。另有研究者觀察到給CIA大鼠灌服MEK抑制劑PD184352阻滯ERK活化，能產(chǎn)生與FR180204相似的改善關(guān)節(jié)病變的療效[30]。動物實(shí)驗(yàn)的結(jié)果令人振奮，ERK可能成為治療RA的新靶點(diǎn)，而其抑制劑有望成為緩解RA癥狀，甚至阻斷病情進(jìn)展的新型藥物[31]。雖然當(dāng)前ERK抑制劑的安全性還沒有得到充分的論證，還要做更多更深入的研究，但嘗試研制可經(jīng)口服的、具有臨床應(yīng)用潛質(zhì)的ERK抑制劑是非常有必要，也是頗具廣闊前景的。

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ERKsignalingpathwayinrheumatoidarthritis

WANG Jian-zhu, KONG Xiang-ying, LIN Na

(InstituteofChineseMateriaMedica,ChinaAcademyofChineseMedicalSciences,Beijing100700,China.E-mail:linna888@163.com)

The excessive activation of extracellular signal-regulated kinase(ERK) signaling pathway, which is a significant feature of rheumatoid arthritic(RA) arthropathy, plays an important role in the process of synoviocyte dysfunction and destruction of cartilage and bone. Understanding the pathomechanism of ERK signaling in RA provides a new target for developing new drug and therapeutic strategy. This review summarizes the current knowledge of the activation, regulation and function of ERK pathway, and also analyzes the role of this signaling transduction in the destruction of joints and the pathogenesis of RA.

Extracellular signal-regulated kinases; Arthritis, rheumatoid

R363

A

10.3969/j.issn.1000-4718.2011.02-037

1000-4718(2011)02-0398-05

2010-05-11

2010-08-25

北京市自然科學(xué)基金資助項(xiàng)目(No.7062051);國家自然科學(xué)基金資助項(xiàng)目(No.30672647);國家科技重大專項(xiàng)課題-重大新藥創(chuàng)制基金資助項(xiàng)目(No.2009ZX09301-005-007；No.2009ZX09502-019)

△通訊作者 Tel: 010-64011692; E-mail: linna888@163.com